Harvey S. Bartnof, MD

This report includes highlights from the 3rd International Workshop on Salvage Therapy for HIV Infection held April 12-14, 2000, in Chicago, and the 10th International Symposium on Viral Hepatitis and Liver Disease held April 9-13, 2000, in Atlanta. The Atlanta conference featured a few reports about coinfection with HIV and hepatitis C virus (HCV), an increasingly important issue in the HIV/AIDS pandemic.

What Is Salvage Therapy?

Experienced HIV researchers and clinicians at the Salvage Workshop discussed what salvage therapy means. Some believed it referred to a second-line regimen of therapy after having HIV viral rebound or never achieving viral undetectability with the first anti-HIV regimen. Others believed it referred to HIV positive persons who had detectable HIV RNA after several regimens that collectively represented all three anti-HIV drug classes. No consensus was reached, and salvage therapy is currently a nonspecific term. When seeing salvage therapy in connection with treatment for HIV, it is important to ascertain the specific anti-HIV drug history of the HIV positive persons in the study.

On the second day, the issue was extended to a discussion about the title of the workshop. John Mellors, MD, of the University of Pittsburgh and conference co-chair, led the discussion. A few community representatives were present. Some people felt that the term salvage has a negative connotation and that the title of the workshop should be changed. Some expressed the opinion that potentially negative terms, such as salvage, rescue (therapy), and (drug) failure, should not be used in the title. Dr. Mellors said that the organizing committee would attempt to resolve the issue after the workshop had concluded. It is possible that the title of next year's workshop will be different.

Why Is Salvage Therapy Important?

Unfortunately, only half of HIV positive persons achieve and maintain an undetectable HIV RNA viral load with their first regimen. (The exception to this would be higher rates of undetectability in a few more recent studies, such as combination regimens based on lopinavir/ritonavir [ABT-378/Norvir; the combination of the two drugs is now called Kaletra] or efavirenz [Sustiva].) As a general rule, the likelihood of achieving undetectability decreases with each successive anti-HIV regimen. Thus, finding a salvage regimen that will be successful in achieving and maintaining an undetectable viral load is important. The best combination and strategy will not necessarily be the same for every person with HIV.

How Successful Are Salvage Therapy Regimens?

Several speakers reported results of studies with second-, third-, or even fourth-line treatment regimens. Some results were discouraging, some more promising.

Five-drug salvage regimen leads to 78% viral undetectability after 60 weeks

Michael Youle, MBChB, of the Royal Free Centre for HIV Medicine in London, UK, presented the results of a study that had one of the better virologic success rates. The 92 people (13% women) who participated in the study had had previous virologic failure (at least 1,000 copies/mL of HIV RNA) with at least one regimen that contained a protease inhibitor (PI). All were hospitalized as a part of induction (initiation) therapy with a mean of five anti-HIV drugs. Even though 17% had previously taken nevirapine (Viramune), none had taken efavirenz. Both drugs are non-nucleoside reverse transcriptase inhibitors (NNRTIs).

All study subjects were hospitalized during treatment induction. A specially designated health-care team included some who closely communicated with subjects to maximize adherence of doses and to help manage side effects. The number of physicians prescribing medications was strictly limited, to limit the number of therapeutic approaches and variability in prescribing.

The most common five-drug combination was efavirenz/ritonavir (Norvir)/indinavir (Crixivan)/ddI (Videx)/hydroxyurea (Hydrea). Hydroxyurea is an anticancer drug also used to treat sickle cell anemia. It was common for the physician and subject to agree to stop an intolerable drug in the regimen. The most commonly discontinued drug among the five was hydroxyurea.

The percentage of people who started each anti-HIV drug was as follows: efavirenz (100%), ddI (80%), ritonavir (75%), hydroxyurea (75%), indinavir (73%), d4T (Zerit) (36%), 3TC (Epivir) (26%), saquinavir soft gel (Fortovase) (16%), nelfinavir (Viracept) (12%), AZT (Retrovir) (5%), and abacavir (Ziagen) (5%). Doses of indinavir/ritonavir were either 800/200 or 800/400 mg, respectively, twice daily. Interestingly, some participants also received intravenous (IV) foscarnet (Foscavir) as an additional anti-HIV drug, even though it is FDA-approved to treat cytomegalovirus (CMV) infection (a common cause of blindness) and not HIV. The median time of follow-up in this observational trial was 41 weeks. The median frequency of viral load testing was once every 6.7 weeks. Some had periods of treatment interruption, but specifics were not reported.

Discontinuation of at least one drug due to adverse events occurred in 37%. Dr. Youle did not mention the various types of adverse events. Ten subjects (11%) did develop new AIDS-defining conditions during the study.

The initial results in this study were impressive, although with a strong trend toward viral rebound. However, the regimen and strategy might be used to buy time until newer medications or strategies are available. Dr. Youle believes that the favorable outcomes were due to several specific factors: hospitalization for induction therapy; the initial inclusion of hydroxyurea; higher doses of indinavir/ritonavir; a specially devoted staff who were constantly in communication with study subjects to optimize adherence and manage side effects; treatment interruptions; intensification with 3TC, if appropriate; and a limited number of physicians prescribing medications.

There were some limitations in the study as it was presented. Dr. Youle was not specific about several factors that would have been helpful to know. Examples are the average number of drugs discontinued and when they were discontinued, the rate of dose reductions, the rate and duration of treatment interruptions, types of adverse events, and whether those who had CD4 cell count increases maintained or had additional increases or even decreases. Some measurement of adherence would have been useful. Also, baseline drug resistance testing, if it had been performed, would have been relevant, including its relationship to virologic outcome.

As was emphasized later at this workshop, the potential for adverse drug concentrations increases with increasingly complex anti-HIV regimens. It is quite possible that virologic failure in this study was associated with blood levels of anti-HIV drugs that were subtherapeutic (too low). In addition, in an era of managed care in the U.S. and elsewhere, access to hospitalization for induction therapy and specially dedicated staff for constant communication are unlikely luxuries. The additional costs of those components will surely increase the overall cost of care for persons with HIV. Lastly, quality-of-life measurements of participants would have been helpful.

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ACTG 359

This complex study, presented by Roy M. Gulick, MD, of Cornell University, included six study arms. (ACTG stands for AIDS Clinical Trials Group.) A factorial design (a particular type of statistical analysis) was used to compare different combinations of drugs. The 277 HIV positive persons had at least 2,000 copies/mL of HIV RNA after more than six months of indinavir combination therapy. None had taken NNRTIs. The six arms of the study were

The median baseline HIV RNA viral load was 4.5 log (31,746) copies/mL, with a median CD4 cell count that was not reported in the abstract. At 16 weeks, only 30% had an undetectable viral load (limit of 500 copies/mL). The percentages with an undetectable viral load were (1) 33%, (2) 20%, (3) 31%, (4) 47%, (5) 16%, and (6) 38%. Statistical analyses showed a significantly greater proportion with undetectable virus in the delavirdine-containing arms than in the adefovir-containing arms. However, no significant difference appeared when comparing the three ritonavir-containing arms with the three nelfinavir-containing arms. Also, there was no significant difference when comparing the delavirdine-containing (without adefovir) arms with the delavirdine plus adefovir-containing arms. Among the 30% who had an undetectable viral load at 16 weeks, only 55% of them (17% of the total) still were undetectable at week 48. CD4 cell count changes were not reported in the abstract.

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ACTG 398

The results of this study were presented by John Mellors, MD, of the University of Pittsburgh. ACTG 398 was designed to determine whether a second PI would be helpful when added to a salvage regimen that included standard doses of amprenavir (1,200 mg twice daily), abacavir (300 mg twice daily), efavirenz (600 mg once daily), and adefovir (60 mg once daily with L-carnitine daily).

After 24 weeks, 31% had an undetectable viral load (limit of 200 copies/mL), with rates in the four arms that were (1) 34%, (2) 36%, (3) 34%, and (4) 23%. A strict intent-to-treat analysis was used. When comparing the placebo arm (4) to all three of the double PI drug arms, the results were statistically significant. Also, a significantly greater percentage achieved undetectability if there had been no previous NNRTI experience (43%) than among those with previous NNRTI experience (16%). There also was a trend toward a higher undetectability rate among those with one PI drug experience than among those with multiple PI drug experience. At 24 weeks, 7% of enrollees had discontinued from the study, 33% were off drugs due to toxicity, and 19% were off study due to detectable viral load. CD4 cell count changes were not reported in the abstract.

Dr. Mellors concluded that HIV undetectability at 24 weeks was only 31%, despite four to five new anti-HIV drugs. Also, the dual PI drugs arms performed better than the placebo or single PI drug arm. In addition, prior experience with NNRTI drug(s) was significantly associated with inability to achieve viral undetectability, while prior PI experience (at least two PIs) was marginally associated with a poorer virologic outcome than experience with only one PI drug. Lastly, the off-treatment rates were high, indicating that "more effective and better tolerated salvage regimens are needed."

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Multi-Drug Rescue Therapy

Julio Montaner, MD, from the British Columbia Centre for Excellence in HIV/AIDS in Canada, presented an update of his multi-drug rescue therapy (MDRT) among heavily pre-treated individuals with HIV. This group had more treatment experience than in the studies described above. The MDRT protocol called for using up to nine "recycled" anti-HIV drugs as a part of the new regimen. This included up to four NRTIs, two PIs, and two NNRTIs, with or without hydroxyurea. The 245 persons enrolled in the study were divided into three different time periods. Group I was enrolled before June 1998, Group II between July and December of 1998, and Group III between January and May of 1999. All three groups had an approximate median baseline viral load of 4.8 log (56,500-63,700) copies/mL. The median number of anti-HIV drugs that was started for each group was (I) five, (II) seven, and (III) six.

After 47 to 57 weeks, 40% of Group I achieved viral load undetectability (limit of 400 copies/mL) using a strict intent-to-treat analysis. After 25 to 35 weeks, 44% of Group II and 34% of Group III had an undetectable viral load (same limit). However, toxicity was very high, and many participants had to stop part or all of their therapy for varying durations. For Group I, baseline phenotype drug resistance testing revealed that sensitivity (not resistance) to 3TC, d4T, ddI, and saquinavir (Fortovase) was significantly correlated with a favorable virologic response. (Phenotypic drug resistance testing measures HIV growth of a person's dominant strain when each of the FDA-approved drugs is added. To do this, the reverse transcriptase and protease genes are removed from the person's HIV strain and subsequently inserted into a laboratory HIV strain.)

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Indinavir plus Ritonavir Four-Drug Combination

One salvage study with better results than most was presented by Howard Grossman, MD, from New York City. In order to achieve a higher level of indinavir with fewer side effects, 800 mg of the drug were combined with 200 mg of ritonavir, each twice daily in combination with a median of two NRTIs, with or without an NNRTI. The twice-daily dosing with 800 mg indinavir plus 200 mg ritonavir achieves even better drug concentrations than occurs with the previously popular dose of 400 mg of each, twice daily. The pharmacokinetics (drug concentration, metabolism, and distribution within the body) of these dual PI regimens are significantly improved with increased minimum (trough) and area-under-the-curve (AUC, or total drug exposure) concentrations and a mild decrease in the maximum, or peak concentration (compared with indinavir monotherapy with standard dosing). Also, there are no food restrictions, fluid requirements, or reported kidney stone complications with either dual-PI drug combination regimen.

This small study with 41 participants (no women, 27% non-White) was open-label and was analyzed retrospectively by chart review. The study took place at three clinics. The regimen was second-line, or salvage therapy. Included were those who had taken the newer indinavir/ritonavir dosing above, in combination with a median of two NRTIs (with or without an NNRTI) for at least eight weeks after having had a detectable viral load previously with at least one PI drug combination. Before entry into the current study, all enrollees had taken a mean of six anti-HIV regimens. Seventy-three percent had previously taken an NNRTI.

Using the twice-daily dosing of both indinavir 800 mg and ritonavir 200 mg with NRTI drug(s), with or without an NNRTI, in a highly therapy-experienced group, appeared to be promising based on this retrospective and small study. The rates of viral undetectability were good, and were similar to those in treatment-naive persons.

Unfortunately, the authors did not report their results when controlling for those who had taken an NNRTI in their new regimen and for those who had had prior experience with that drug class. It is quite possible that adding an NNRTI into the regimen of those without experience to that drug class might have represented a major proportion of those who had HIV RNA undetectability. However, such subsets would have had only small numbers of subjects, limiting statistical analysis. Another limitation was the small size of the study and short follow-up. Also, the study is retrospective (after the fact), which carries less weight than a prospective and preferably randomized study. Lastly, drug resistance tests were not reported and possibly not performed. Baseline drug resistance tests might have added predictive value as to which persons would respond. Additional follow-up is expected, since the study is ongoing. The authors anticipate that more people will be enrolled.

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This year Dr. Miller presented additional information about the original group of 39 participants. Thirty-three had a virologic response to a new anti-HIV regimen after the interruption. The mean follow-up time after responding was 385 days. Among the responders, 24 (73%) did have subsequent viral rebound within a median of 78 days. There was a nonsignificant trend toward a more durable virologic response with the new regimen among the "shifters" (25% maintained viral undetectability) than among "nonshifters" (none maintained undetectability). Immunologically, 74% did achieve a return of CD4 cell count to within 90% of the preinterruption level after a new regimen was started. However, a median duration of 251 days (more than eight months) was required to reach that endpoint.

Then, Dr. Miller reported observations during a treatment interruption of at least two months among a larger, expanded group of 165 participants (21% women) using the entire Frankfurt cohort of persons with HIV infection. Another requirement for being included in this new group was a history of a viral rebound to at least 5,000 copies/mL during the interruption, after having taken a regimen of at least three anti-HIV drugs.

After the CD4 cell nadir, the mean follow-up time was 408 days. In this larger group of 165 subjects, 64% did respond to a new regimen after the treatment interruption. However, 86% of them subsequently had HIV viral rebound. Dr. Miller then presented correlates of those findings. Those with higher CD4 cell counts at the start of the interruption were significantly less likely to have viral rebound; in contrast, those with a lower CD4 cell nadir were significantly more likely to have rebound. Unfortunately, drug resistance results were not included in the analyses. Therefore, the results of the current multivariate analyses might be misleading, since they could be different after the resistance information is included.

In this expanded group of participants, 75% did have a recovery of CD4 cell count to within 90% of the pre-interruption level after starting a new regimen. However, the median time was three months, compared with eight months for the original smaller cohort. During the treatment interruptions, 17 documented new AIDS-defining conditions occurred in 15 different participants. Those included five different types of opportunistic infections (OIs), wasting syndrome, encephalopathy (brain disease), and Kaposi's sarcoma (KS, a cancer primarily due to human herpesvirus type 8 [HHV8]).

Much is still unknown about treatment interruptions, but several ongoing studies will help to clarify the potential benefits and related risks with this very experimental approach to treating persons with HIV infection. In her next round of analysis, Dr. Miller will be able to include the resistance data of the expanded group that is being analyzed.

WARNING: Drug treatment interruptions are risky. For most people, the HIV RNA viral load increases and the CD4 cell count decreases. The decreased CD4 cell count might place many at risk for AIDS-defining, life-threatening OIs. Note that this happened to some of Dr. Miller's study subjects. Another risk is that HIV might be able to seed previously uninfected cells or reseed different types of immune cells and various body compartments. Theoretically, this might make HIV eradication in the future more difficult, when and if a cure is discovered. Do not start a treatment interruption without discussing the issue fully with a physician.

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New Drug Resistance at a Low Viral Load May Predict Viral Rebound

Neil T. Parkin, PhD, of ViroLogic in South San Francisco, CA, presented the results of a small, 16-person study about predicting virologic failure with a new regimen. In ten people who experienced viral rebound, new drug resistance mutations at a low viral load (fewer than 1,000 copies/mL) were detected. In six other people, who did not experience rebound after at least 24 weeks, new drug resistance mutations were not detected.

The study was a retrospective analysis using the PhenoSense HIV phenotype drug resistance test. Genotypic resistance testing also was performed for additional correlations. (Genotypic drug resistance testing evaluates the presence or absence of gene mutations in a person's dominant HIV strain that previously have been associated with resistance to the drug being tested or the class of the drug being tested.)

The 16 study subjects originally had a detectable viral load with their first PI-containing regimen. Then, they were switched to a four-drug regimen: (1) nelfinavir (1,250 mg twice daily, PI drug); (2) saquinavir soft gel (1,200 mg twice daily, PI drug); (3) abacavir (NRTI drug); and (4) either one other NRTI drug or nevirapine (NNRTI drug). Blood samples were evaluated periodically for drug resistance.

Dr. Parkin's results were that drug resistance could be measured at a level as low as 260 copies/mL. In the ten participants who had drug failure, all had HIV that was susceptible to one to three drugs at baseline. Yet, at the time of their drug failure, 100% developed resistance to one to three drugs in their respective regimens. The duration until new drug resistance developed ranged from 4 to 36 weeks. Also, the time to drug failure was 4 to 26 weeks. Drug resistance was detected before drug failure in 70% and simultaneously in the other 30%. (Several weeks elapsed between blood samplings. Therefore, drug resistance might have developed prior to drug failure in this 30%; however, there was no blood sample for proof.) Eleven weeks was the longest interval between detecting drug resistance and drug failure. No new mutations were detected in the six people who maintained viral undetectability (limit of 50 copies/mL). Detecting new resistance at a low viral load might allow for intervening with drug intensification or a change of the regimen with the goal of potentially avoiding continued rebound in the future.

This small study was a retrospective analysis, which carries less statistical weight than a prospective analysis. A larger, prospective study is therefore needed to establish the implications of this trial. If finding resistance at a low viral load and intensifying or changing the regimen led to long-term viral undetectability, then more frequent viral load testing might significantly benefit people with HIV infection. A separate cost analysis would help to determine whether more frequent testing would fall into a range of comparable cost-effective interventions in health-care delivery. Notwithstanding these limitations, Dr. Parkin's results are provocative and might have tremendous implications for persons with HIV.

Negative Drug Interaction with Amprenavir and Efavirenz Is Avoided by Adding Ritonavir

Jean-Louis Vilde, MD, of the Hôpital Bichat in Paris presented the results of a study indicating that the triple combination of amprenavir/efavirenz/ritonavir avoids the negative interaction when the first two are used alone. In that situation, amprenavir levels in blood are reduced significantly by efavirenz. However, adding low-dose ritonavir and also reducing the amprenavir dose leads to an even higher amprenavir blood level than with amprenavir monotherapy using the FDA-approved dose of 1,200 mg twice daily. The doses of the three drugs in Dr. Vilde's presentation were amprenavir 450 mg twice daily, ritonavir 100 mg twice daily, and efavirenz 600 mg once daily. The example used the three drugs in combination with two NRTI drugs.

After two weeks in the current study, seven persons had a steady-state (stable) minimum concentration of amprenavir that was 1,380 nanograms/mL, approximately five-fold higher than what is achieved with standard dosing of amprenavir without ritonavir. That level in the current study is ten-fold higher than the IC50 (concentration that will inhibit 50% of HIV growth in the laboratory) of drug resistant HIV and thirty-fold higher than the IC50 of wild-type HIV. Also, the variability of the minimum concentration among study subjects was significantly less than it was during the first two weeks. Dr. Vilde did not present AUC concentration results. However, in the few studies to date that have examined this issue for PI drugs, the minimum concentration was a better determinant of anti-HIV benefits than the AUC concentration. Increasingly, physicians have been starting people on a double PI drug regimen (rather than a single PI drug in combination) in which one drug is ritonavir, or adding it to an existing single PI drug-based regimen.

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Oral L-Acetyl Carnitine Improves HIV-Related Peripheral Neuropathy

Michael Youle, MBChB, presented a very interesting report about treatment for peripheral neuropathy (tingling/numbness/burning in the feet and sometimes hands). This condition is present in 33% of persons with HIV infection. It is also a common side effect of the "d" drugs in the NRTI drug class -- ddC (Hivid), ddI, and d4T.

The treatment for mild peripheral neuropathy (i.e., that does not interfere with everyday functioning) in people taking any of the "d" NRTI drugs is to stop that medication(s). Other treatments help to ease the symptoms, including amitriptyline (Elavil, an antidepressant drug), lamotrigine (Lamictal, an anti-seizure drug), topical lidocaine (Lidoderm), or pain relievers (acetaminophen or Tylenol, NSAIDs [non-steroidal anti-inflammatory drugs, including Motrin and Aleve]) that might include narcotics. Recombinant (manufactured) human nerve growth factor is an experimental treatment. Acupuncture may also help.

Dr. Youle's small observational study treated HIV-related peripheral neuropathy with oral L-acetyl carnitine (LAC). He found that 1,500 mg twice daily of the supplement orally led to improved symptoms after several months. The improvement in symptoms was associated with an increase in nerve tissue staining on biopsy samples from four subjects. This was accomplished using immunohistochemical (IHC) staining of nerve tissue. IHC uses a dye that is tagged with antibodies directed against nerve tissue. A previous study showed abnormally decreased IHC staining of nerve tissue even before numbness and tingling symptoms occurred in HIV negative diabetics who subsequently were diagnosed with peripheral neuropathy.

LAC naturally occurs in the body and is derived from the amino acid carnitine. It facilitates the normal oxidation and movement of free fatty acids into mitochondria within cells. LAC also helps to maintain living nerve cells in tissue culture in the laboratory. In a diabetes animal model of peripheral neuropathy, supplementing the diet with LAC improved the neuropathy. In a separate study, LAC improved nerve regeneration. Interestingly, in those who are HIV positive with peripheral neuropathy due to d4T, ddI, or ddC, blood serum (liquid portion without cells) shows abnormally low levels of LAC. Previously, one small study showed that LAC supplements in persons with HIV-related peripheral neuropathy improved symptoms.

In the current study, three HIV positive persons with peripheral neuropathy continued the same regimen without stopping their NRTI drug(s). Skin biopsies with nerve tissue were taken from the lower leg at baseline and six months after starting LAC therapy. The biopsies were stained by IHC for "innervation" by three types of nerve fibers: (1) small sensory C and A-delta fibers (CGRP), (2) pan-neuronal fibers (PGP 9.5), and (3) cholinergic efferent sympathetic fibers (VIP). The area of staining for each biopsy was measured by computer using quantitative image analysis.

Dr. Youle showed pictures of representative biopsy samples that were stained by IHC and measured. Tissues examined included sweat glands in the skin that normally have nerve tissue attachments (innervation), the epidermis (top skin layer), and dermis (lower skin layer). Comparisons of the stained biopsies from his study participants before and after LAC showed an increase in staining, both in percentage of area stained and in intensity of staining. The changes in the biopsy samples were accompanied by improvements in participants' symptoms of peripheral neuropathy, particularly dysaesthetic ("phantom") pain. Several months of LAC therapy were required before symptoms improved. Dr. Youle said that one of his participants had required narcotic pain medication before LAC and no longer needed it several months after LAC therapy.

In his clinic, Dr. Youle has about 60 to 70 people taking LAC for HIV-related peripheral neuropathy. The only adverse symptom reported is mild diarrhea. Dr. Youle did not say whether participants had any changes in standard blood or urine tests or in viral load. He did not know whether LAC entered the cerebrospinal fluid (CSF) around the brain and spinal cord or whether it might benefit AIDS-related dementia (loss of brain function). He emphasized, however, that L-acetyl carnitine is not the same as carnitine that is commonly available in many vitamin stores as a dietary supplement.

As this article goes to press, long-term larger studies using LAC have not been reported. The exact dose is unknown, as are potential toxicities that would be revealed only in larger studies. Also, adverse drug interactions, particularly with anti-HIV medications, are unknown. Persons with HIV should always discuss with their physicians before taking any medication or supplement.

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De Simone, C. and others. Carnitine depletion in peripheral blood mononuclear cells from patients with AIDS: effect of oral L-carnitine. AIDS 8(5):655-60. May 1994

Famularo, G. and others. Acetyl-carnitine deficiency in AIDS patients with neurotoxicity on treatment with antiretroviral nucleoside analogues. AIDS 11(2):185-90. February 1997

Famularo, G. and others. Carnitine stands on its own in HIV infection treatment. Archives of Internal Medicine 159(10):1143-4. May 24, 1999

Virmani, M.A. and others. Protective actions of L-carnitine and acetyl-L-carnitine on the neurotoxicity evoked by mitochondrial uncoupling or inhibitors. Pharmacologic Research 32(6):383-9. December 1995

Study entry required starting highly active antiretroviral therapy (HAART) between August 1996 and December 1998 in British Columbia. HAART meant two NRTI drugs and either a PI or an NNRTI drug. Drug adherence was defined by the following percentage: dividing the number of months that anti-HIV drugs were dispensed by the pharmacy during the first year of HAART by the total number of months of follow-up in the first year of HAART. Nonadherence was measured for each 10% decline in drug adherence. Participants had had no previous treatment.

A total of 950 people (15% women) met the study criteria and were included in the analysis. Median HAART duration was 13 months. During that time, 64 participants died and 11 were diagnosed with primary AIDS.

The researchers used a multivariate statistical model to obtain their results. Death was independently associated with being nonadherent to anti-HIV dosing. The statistical "adjusted relative risk" of death with not being adherent was 1.16 (i.e., 16% increased risk). Also, the risk of death was associated with a lower baseline CD4 cell count. The results of nonadherence were the same when an AIDS diagnosis was used as an endpoint. All of these results reached statistical significance, and they indicate the importance of strictly adhering to all doses of anti-HIV therapy.

One limitation of the study is the fact that receiving medications from the pharmacy does not necessarily mean that participants took all doses. Yet people are less likely to request a medication refill if they do not plan to use it.

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Montessori, V. and others. Non-adherence to triple combination therapy is predictive of AIDS progression and death in HIV positive men and women. 3rd International Workshop on Salvage Therapy for HIV Infection. Chicago. April 12-14, 2000. Abstract and oral/poster presentation 28.

HIV Deaths in the U.S. Are Increasingly Associated with Liver Disease

Recent reports have shown that coinfection with HCV has been present in an increasing percentage of persons with HIV infection in the U.S. That rate currently is approximately 33%, although it closely tracks with the percentage who acquired HIV by injection drug usage. Also, a few reports have concluded that in persons with HIV infection, coinfection with HBV or HCV represented a risk factor for liver enzyme increases after HAART was started.

Death certificates were examined using the U.S. National Vital Statistics System. The National Center for Health Statistics maintains that database using standardized ICD-9 diagnosis codes. Each person who dies in the U.S. must have a death certificate signed by that person's physician, a coroner, or a medical examiner. Certificates list the cause(s) of death, including contributory causes (such as HIV infection) and secondary causes (such as AIDS-related OIs).

Among deaths in persons with HIV, the percentage who had liver disease listed on their death certificates had increased between 1987 and 1997 from approximately 3% to 10%. The increases were greater after 1995, compared with the years between 1987 and 1995. Note that the PI drugs were widely introduced in the U.S. after 1995.

In persons with HIV, the percentage that had any one of several liver-related diagnoses increased from 1987 to 1997. Those categories included chronic liver disease, non-A/non-B hepatitis, HBV, nonalcoholic-related cirrhosis (scarring), and unspecified disorders of the liver. (Other studies have indicated that most non-A/non-B hepatitis during that time period would be due to HCV, although there was no FDA-approved blood test for HCV until 1990.) Adding up the percentages from all of those liver conditions, the totals come to approximately 3% in 1985, 5% in 1987, and 10% in 1997.

Dr. Selik commented, "The surge in the percentage of deaths with liver disease after 1995 coincides with the introduction and increased use of protease inhibitors to treat HIV infection, possibly reflecting a hepatotoxic [liver toxicity] effect of these drugs." He continued, "Such toxicity may be insufficient to cause fatal liver disease by itself, but it may aggravate the severity of liver diseases due to other causes, such as [viral] hepatitis." Also, it should be emphasized that association does not necessarily mean causation.

The researchers acknowledged a few limitations in their report. First, the increase in reported liver disease on death certificates among persons with HIV might be due to an increased use of HCV tests that were first approved in 1990. Second, the increasing percentage of persons with HIV who were dying with liver disease might be due to a decrease in the number of deaths due to AIDS-related OIs. Reasons could be improved immunity due to HAART, effects from antibiotic prophylaxis (prevention) therapy, or both. Third, liver toxicity might be due to other drugs that are part of HAART regimens or possibly antibiotic prophylaxis. However, this is less likely, since antibiotic prophylaxis and NRTI usage was common before the 1995-1997 period when the rate of liver disease on death certificates in persons with HIV rose significantly. Lastly, the results could be caused by a cohort effect -- if a significant proportion of persons with HIV infection became infected with HBV or HCV in the late 1970s, then an increased proportion of deaths associated with liver disease might be due to a delay of 15 years or longer until liver complications begin to appear.

A total of 381 persons with HIV infection were evaluated in the first report that was authored by Dr. S. George and colleagues. Excluding 106 participants (28%) who were HCV antibody positive, 17 (6%) had a positive HCV RNA test on more than one occasion. (The Abbott enzyme immunoassay [EIA] version 2.0 was the antibody test used, while an "in-house" RT-PCR, or reverse transcriptase-polymerase chain reaction test, was used to detect HCV RNA.) Using the Roche Monitor HCV RNA test, three of the nine who tested positive by the RT-PCR test also tested positive with the commercial assay. There was no relationship between HCV RNA positivity/HCV antibody negativity and any of the following: CD4 cell count, HIV RNA level, age, gender, or alanine aminotransferase (ALT) liver enzyme level. However, more than twice the number in this group had a history of injection drug use (18%) than did the HCV RNA negative group (7%).

One limitation was that some of the people with HIV and a false negative antibody test for HCV could have been recently infected with HCV (during the "window" period) and subsequently would have developed a positive antibody test result. Another limitation is that an in-house HCV RNA test was used. It is possible that this test would not be as reliable as a test kit from a commercial manufacturer. Lastly, a history of or concurrent anti-HIV therapy was not mentioned as a potential confounding cofactor.

People with HIV infection normally have a screening test for HBV infection, usually HBV surface antigen. If negative, most clinicians would not perform any other tests for HBV. In a second study from the University of Iowa, authored by Dr. J. Xiang and colleagues, some persons with HIV and a negative HBV surface antigen test had detectable HBV DNA. This indicates active HBV infection.

A total of 491 persons with HIV infection were tested for HBV DNA in blood serum and plasma by using polymerase chain reaction (PCR). Seventy (14%) had HBV DNA that was detectable on multiple samples, indicating active HBV infection. Only 48 of those 70 persons had results in their chart of three HBV tests including surface antigen, core antibody, and HBV DNA. Among those 48 people, 19 (40%) had a negative test for HBV surface antigen. Moreover, nine out of those 19 were negative for both HBV surface antigen and HBV core antibody.

There were several limitations in this report. First, the mean HBV DNA results were not presented. It is possible that those coinfected subjects with serosilent HBV infection had lower (or higher) HBV DNA levels than those with seropositive HBV infection. This might help to explain the findings, but would not necessarily change the conclusions. Second, anti-HIV therapy as a cofactor was not mentioned. While the number of persons was small, it is possible that a higher percentage of HIV/HBV coinfected persons with more typical HBV seropositive tests were more likely to be taking anti-HIV therapy than those with serosilent HBV infection. This could have been one reason why HBV seropositive people had a higher mean CD4 cell count than those who were serosilent. Third, the authors did not indicate whether HIV viral load was a potential cofactor. Fourth, age as a potential cofactor was not mentioned.

The results of these two studies need confirmation in a larger number of people. If still present, the findings are significant for HIV positive persons. The conclusions suggest that in persons with HIV infection: (1) HBV DNA testing should be performed on HIV positive persons with negative tests for HBV surface antigen and core antibody, and (2) HCV RNA testing should be performed if the HCV antibody test is negative. In addition, the findings have potential implications for possible hepatitis virus transmission (HBV and/or HCV) through sharing needles and sexual partners, when the source person might have been told that he or she was negative.

Page last updated 31 August 2000